Lung cancer is the most common form of cancer in the world. Typical diagnosis of lung cancer combines x-ray with sputum cytology. Unfortunately, by the time a patient seeks medical attention for their symptoms, the cancer is at such an advanced state it is usually incurable. Consequently, research has been focused on early detection of tumor markers before the cancer becomes clinically apparent and while the cancer is still localized and amenable to therapy.
The World Health Organization has classified lung cancer into four major histological or morphological types: (1) squamous cell carcinoma, (2) adenocarcinoma, (3) large cell carcinoma, and (4) small cell lung carcinoma. (World Health Organization. 1982. "The World Health Organization Histological Typing of Lung Tumors," Am J Clin Pathol 77:123-136). However, there is a great deal of tumor heterogeneity even within the various subtypes, and it is not uncommon for lung cancer to have features of more than one morphological subtype. The term "non-small cell lung carcinoma" (NSCLS) has been used to distinguish squamous carcinomas, adenocarcinomas, and large cell carcinomas from small cell lung carcinomas.
Particular interest has been given to the identification of antigens associated with lung cancer. These antigens have been used in screening, diagnosis, clinical management, and potential treatment of lung cancer. For example, carcinoembryonic antigen (CEA) has been used as a tumor marker of cancer including lung cancer. (Nutini, et al. 1990. "Serum NSE, CEA, CT, CA 15-3 levels in human lung cancer," Int J Biol Markers 5:198-202). Squamous cell carcinoma antigen (SCC) is another established serum marker. (Margolis, et al. 1994. "Serum tumor markers in non-small cell lung cancer," Cancer 73:605-609). Other serum antigens for lung cancer include antigens recognized by monoclonal antibodies (MAb) 5E8, 5C7, and 1F10, the combination of which distinguishes between patients with lung cancer from those without. (Schepart, et al. 1988. "Monoclonal antibody-mediated detection of lung cancer antigens in serum," Am Rev Respir Dis 138:1434-8). Serum CA 125, initially described as an ovarian cancer-associated antigen, has been investigated for its use as a prognostic factor in NSCLC. (Diez, et al. 1994. "Prognostic significance of serum CA 125 antigen assay in patients with non-small cell lung cancer," Cancer 73:136876). Other tumor markers studied for utilization in multiple biomarker assays for lung cancer include carbohydrate antigen CA19-9, neuron specific enolase (NSE), tissue polypeptide antigen (TPA), alpha fetoprotein (AFP), HCG beta subunit, and LDH. (Mizushima, et al. 1990. "Clinical significance of the number of positive tumor markers in assisting the diagnosis of lung cancer with multiple tumor marker assay," Oncology 47:4348; Lombardi, et al. 1990. "Clinical significance of a multiple biomarker assay in patients with lung cancer," Chest 97:639-644; and Buccheri, et al. 1986. "Clinical value of a multiple biomarker assay in patients with bronchogenic carcinoma," Cancer 57:2389-2396).
Monoclonal antibodies (MAb) to the antigens associated with lung cancer have been generated and examined as possible diagnostic and/or prognostic tools. For example, MAbs for lung cancer were first developed to distinguish non-small cell lung carcinoma (NSCLC) which includes squamous, adenocarcinoma, and large cell carcinomas from small cell lung carcinomas (SCLC). (Mulshine, et al. 1983. "Monoclonal antibodies that distinguish non-small-cell from small-cell lung cancer," J Immunol 121:497-502). MAbs have also been developed as immunocytochemical stains for sputum samples to predict the progression of lung cancer. (Tockman, et al. 1988. "Sensitive and specific monoclonal antibody recognition of human lung cancer antigen on preserved sputum cells: a new approach to early lung cancer detection," J Clin Oncol 6:1685-1693). U.S. Pat. No. 4,816,402 discloses a murine hybridoma monoclonal antibody for determining bronchopulmonary carcinomas and possibly adenocarcinomas. Other monoclonal antibodies utilized in immunohistochemical studies of lung carcinomas include MCA 44-3A6, L45, L20, SLC454, L6, and YH206. (Radosevich, et al. 1985. "Monoclonal antibody 44-3A6 as a probe for a novel antigen found on human lung carcinomas with glandular differentiation," Cancer Res 45:5808-5812).
Despite the numerous examples of isolated lung cancer antigens and subsequent production of MAb to these antigens, none has yet emerged that has changed clinical practice. (Mulshine, et al., "Applications of monoclonal antibodies in the treatment of solid tumors," In: Biologic Therapy of Cancer. Edited by V. T. Devita, S. Hellman, and S. A. Rosenberg. Philadelphia: J B Lippincott, 1991, pp. 563-588). There is a continuing need to identify specific antigens associated with lung cancer and to generate monoclonal antibodies (MAb) to these antigens for the development of tools for diagnosing cancer, targeting of drugs and other treatments to particular sites in the body, imaging of tumors for radiotherapy, and possible generating therapeutic agents for cancer.
In U.S. Pat. No. 5,589,579 and U.S. Pat. No. 5,773,579, a lung cancer marker antigen specific for non-small cell lung carcinoma was identified and designated HCAVIII. Subsequently, the antigen was renamed HCAXII and finally renamed LCGA. The antigen was found useful in methods for detection of non-small cell lung cancer and for potential production of antibodies and probes for treatment compositions. These patents include the nucleic acid sequence coding for the cell surface protein LCGA (HCAVIII) which is highly specific for non-small cell lung cancer cells as well as isolated proteins encoded by the nucleic acid sequences.
Three monoclonal antibodies specific for LCGA have now been found. These antibodies can be utilized for both in vivo and in vitro clinical diagnosis of non-small cell lung carcinoma and as target selective carriers for various anti-tumor agents and radioimaging agents.